1. Field of the Invention
The present invention relates to neurotrophic and/or neurogenic peptides and their use for manufacturing a medicament for the treatment of tauopathies and related neurodegenerative diseases.
2. Description of the Related Art
Tauopathies are a family of age-associated neurodegenerative diseases which are characterized histopathologically by the abnormal hyperphosphorylation and aggregation of tau in the brain, and clinically by cognitive impairment and or motor. Tauopathies include frontotemporal dementia with Parkinsonism linked to chromosome-17 (FTDP-17) tau, corticobasal degeneration, Pick disease, progressive supranuclear palsy, Guam Parkinsonism dementia complex, dementia pugilistica also known as traumatic encephalopathy or traumatic brain injury, ceroid neuronal lipofusinosis, Hallerworden Sptaz disease, Alzheimer's disease and adults with Down syndrome. The abnormal hyperphosphorylation of tau results in not only the loss of microtubule assembly promoting and stabilizing protein function, but also a gain of toxic function; the abnormally hyperphosphorylated tau sequesters normal tau as well as the other two microtubule associated proteins (MAPs), MAP1 and MAP2, and causes disruption of microtubules.
Alzheimer's disease (AD) is the most common age-dependent neurodegenerative disorder which contributes significantly to health care burden in industrialized countries, especially because of lack of an effective therapy due to its multifactorial and heterogenous nature and involvement of several different etiopathogenic mechanisms. AD is sixth most prevalent cause of mortality in U.S. and leading cause of dementia, affecting over 5 million Americans and 35 million people worldwide. The number of Americans with AD is projected to be 13.5 million by 2050 unless a drug is developed that can prevent or inhibit this disease. Histopathologically, AD is characterized by two major lesions: amyloid as diffuse and neuritic plaques composed of amyloid beta (Aβ) peptide, and neurofibrillary tangles composed of hyperphosphorylated tau protein. Currently, four FDA approved drugs (donepezil, galantamine, rivastigmine, and memantine) available for AD treatment only provide symptomatic benefit with little effect on underlying pathology. Obviously, there is impending urgency to find an effective disease-modifying therapy.
Independent of the various etiopathogenic mechanisms involved in AD, they all cause neurodegeneration. Thus, a successful therapeutic strategy for AD may include both inhibition of neurodegeneration as well as stimulation of regeneration in affected areas of the brain. This shift of balance from neurodegeneration to neural regeneration can be achieved with molecules that promote both neurogenesis and neuronal and synaptic plasticity. By virtue of their neuroprotective and neurogenic capabilities demonstrated in animal models of eurodegeneration, neurotrophic factors represent a promising therapeutic approach for AD. Many studies have shown that neurotrophic factor based approach for AD can ameliorate deficits in neurogenesis, synaptic plasticity, and cognition. However, it is unknown if this strategy could have an effect on underlying Aβ and tau pathologies.
Ciliary neurotrophic factor (CNTF) is a survival factor for various neuronal cell types. The human CNTF protein comprises 200 amino acid residues and shares significant sequence homology with CNTF proteins from other mammalian sources. The gene for human CNTF has been cloned and recombinant forms of the protein are available for clinical trials in humans. Over the past decade, a number of biological effects have been ascribed to CNTF in addition to its ability to support the survival of ciliary ganglion neurons. CNTF is believed to induce the differentiation of bipotential glial progenitor cells in the perinatal rat optic nerve and brain. Furthermore, it has been observed to promote the survival of embryonic chick dorsal root ganglion sensory neurons. In addition, CNTF supports the survival and differentiation of motor neurons, hippocampal neurons and presympathetic spinal cord neurons. The administration of CNTF to the human body has several drawbacks. While its therapeutic potential for CNS diseases is well recognized, the blood brain barrier (BBB) hinders the systemic delivery of CNTF and direct bolus injections are not suitable due to the short half-life of CNTF.